The most common sexually transmitted disease in men is nongonococcal urethritis (NGU). On average, 5 million new cases are reported annually in the United States alone. NGU is a syndromic diagnosis based on the finding of acute inflammation in the urethra. It has been linked to more than 10 different pathogenic species, including trichomonas, candida, herpes, and atypical bacteria. The most important pathogen, found in approximately half of cases, is Chlamydia trachomatis. In half of cases, however, no pathogen is identified.
Several lines of investigation have established Chlamydia trachomatis as the principal cause of NGU. Chlamydia has been isolated as the sole pathogen in 35–50% of cases. It is infrequently found in asymptomatic men. When present, it is usually associated with clear-cut pathology and inflammatory urethral smears. (However, it may also be harbored with minimal symptoms or signs in carriers.) Men with a history of disease have serologic evidence of specific immune response to the infection; and men with acute disease have increasing IgM serologic titers or seroconversion. Transmission of Chlamydia has been demonstrated in over 80% of female contacts of men with the infection, but only 11% of partners of negative men. Treatment with antichlamydial drugs eradicates the organism and cures the disease.
While the role of Chlamydia is well-established, the role of other pathogens is more controversial. The mycoplasmas have long been the subject of much investigation and debate. Ureaplasma urealyticum has been isolated in more than half of cases in some series (Tayler-Robinson, Hooton, Root, Munday, Stefanik). However, it is just as frequently found in completely asymptomatic men. And it is isolated more often in men who are sexually active than those who are not. There are three lines of evidence that have persuaded some, though by no means all, venerologists that Ureaplasma must be playing a role in at least some cases of NGU: 1) evidence from partial treatment trials in which disease recurs after therapy ceases (Shepard); 2) from differential treatment trials in which disease recurs after therapy ceases (Shepard); 3) from differential treatment trials where only one of two susceptible organisms is eradicated and disease persists (Prentice); and 4) from human inoculation and reinoculation trials (Tayler-Robinson). Mycoplasma hominis, although pathogenic in PID and cervicitis, has not been confirmed to cause urethritis. On the other hand, another Mycoplasma strain, Mycoplasma genitalium, has been associated with 15–40% of Chlamydia-negative NGU, and only 19% of controls.
Protozoal infection as a cause of NGU has been considered rare in the developed world. Infection rates are higher in the developing world, with series from Eastern Europe, Africa, Asia and South America reporting in the range of 10–15%. However, a more recent series from Seattle casts doubt on that presumption. Using rigorous methodology including selective cultures, Krieger was able to show Trichomonas vaginalis in 17% of men with NGU(Krieger). Other pathogens such as the anaerobic bacteria are associated with disease in women but not in men. Finally, the viruses, Herpes simplex, Human papillomavirus, and Adenovirus, have been associated, albeit rarely, with NGU. In sum, the known pathogens account for perhaps 40–75% of all cases of NGU.
No diagnosis is determined in 21–60% of cases of NGU (Janier, Jensen, Hooton, Root, Stefanik). While for many years Chlamydia trachomatis infection has been reported in the range of 35–50%, more recently Stamm, and others have pointed to a declining role for this pathogen (Stamm). In a large multicenter 1990 study, only 15% of cases were associated with Chlamydia, and fully 57% were unexplained (Stamm). Interestingly, while the prevalence of Chlamydia is declining, NGU is not. Therefore, the proportion of unexplained cases of NGU may actually be increasing (Zenilman, Schmid).
The reasons put forth for the culture-negative case fall into four broad categories: misdiagnosis, mechanical urethral processes, immunological processes, and unrecognized pathogens. The diagnosis of urethritis can be difficult to establish because of both underdiagnosis and overdiagnosis. The sensitivity of the urethral smear is variable. It may be affected by several factors including: the duration of symptoms, the adequacy of sampling, and the pathogen involved (Arya, Bowie, Landis, Shahmanesh, Swartz, Terry). Urethritis may be overdiagnosed in some men because of the persistence of symptoms after treatment or because of hypervigilance, even in the absence of inflammation (Martin). Some chronic cases of urethritis that are unresponsive to antibiotics may be associated with mechanical urethral problems, although this is rare(Krieger). The not infrequent observation that some men continue to have evidence of inflammation after successful treatment of urethritis has led some investigators to suggest that chronic urethritis, and particularly posttreatment urethritis, may be a consequence of local immunologic processes (Krieger, Martin & Bowie, Hooton, Taylor-Robinson). This is an area of ongoing investigation. Many of these same authorities allude to the possible existence of as yet unrecognized pathogens in NGU (Stamm, Schmid, Oriel, Taylor-Robinson).
In order to prove causality in NGU, Taylor-Robinson has set out several criteria that should be met. First the putative pathogen must be isolated more frequently or be found in greater numbers in men with NGU than in asymptomatic men. Second, when an appropriate antimicrobial agent is administered, and the infection is cleared, the symptoms of the disease must also resolve. Third, there must be objective evidence of an immune response to the offending pathogen. And lastly, the putative pathogen must be transmissible and cause comparable disease in the recipient. Of all the pathogens mentioned above, only Chlamydia trachomatis, Mycoplasma genitalium, and Trichomonas vaginalis fulfill all the criteria for pathogenicity in NGU. Neither a convincing antibody response nor overwhelming association with disease have been demonstrated in the case of Ureaplasma urealyticum. One other important caveat has been put forth by Taylor-Robinson, that a putative pathogen must be shown to be associated with disease in the absence of other pathogens. Numerous prior studies have been undermined by failure to control for other potential pathogens, in particular Chlamydia. 
The treatment of NGU is made more difficult by the frequent absence of a definitive diagnosis. Many clinicians approach it as a syndrome and direct initial therapy at the most likely pathogens, Chlamydia and Ureaplasma. Studies have borne out the effectiveness of this approach in many cases. Doxycycline, long the treatment of choice, is effective against all strains of Chlamydia and most strains of Ureaplasma, although 10% of the latter are resistant. Martin demonstrated that a single dose of Azithromycin was comparable to Doxycycline in the treatment of uncomplicated chlamydial urethritis (Martin). More recently, Stamm and colleagues demonstrated that Azithromycin was overall as effective as Doxycyline, curing 78% of cases of NGU (Stamm). Of some concern, however, was their observation that only 47% of Ureaplasma cases responded to Azithromycin. Nevertheless, the convenience of unit dosing under direct supervision has made Azithromycin the preferred treatment in many STD clinics. Treatment failures have rarely been reported. In one series of treatment failures, Erythromycin cured 52% of men (Hooton). In a smaller series, Flagyl was used in refractory cases with good clinical efficacy (Toth).